chrX-50092130-C-T

Variant names:

• chrX-50092130-C-T
• rs797044814
• NM_001127898.4:c.2362C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_001127898.4(CLCN5):​c.2362C>T​(p.Arg788*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001449234: Functional studies in Xenopus laevis oocytes showed that this nonsense variant produced a truncated protein product and was lower in abundance in comparison to the wild-type. The truncation affected the cellular localisation of the protein (Grand et.al. Kidney Int 2009" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CLCN5 NM_001127898.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.05692
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.29
• Publications: 1 publications found

Genes affected

CLCN5 (HGNC:2023): (chloride voltage-gated channel 5) This gene encodes a member of the ClC family of chloride ion channels and ion transporters. The encoded protein is primarily localized to endosomal membranes and may function to facilitate albumin uptake by the renal proximal tubule. Mutations in this gene have been found in Dent disease and renal tubular disorders complicated by nephrolithiasis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

CLCN5 Gene-Disease associations (from GenCC):

• Dent disease type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0363 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001449234: Functional studies in Xenopus laevis oocytes showed that this nonsense variant produced a truncated protein product and was lower in abundance in comparison to the wild-type. The truncation affected the cellular localisation of the protein (Grand et.al. Kidney Int 2009; 76: 999-1005).; SCV003445154: Experimental studies have shown that this premature translational stop signal affects CLCN5 function (PMID: 19657328).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-50092130-C-T is Pathogenic according to our data. Variant chrX-50092130-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	NM_001127898.4	MANE Select	c.2362C>T	p.Arg788*	stop_gained splice_region	Exon 15 of 15	NP_001121370.1	P51795-2
	CLCN5	NM_001440756.1		c.2374C>T	p.Arg792*	stop_gained splice_region	Exon 15 of 15	NP_001427685.1
	CLCN5	NM_001440757.1		c.2374C>T	p.Arg792*	stop_gained splice_region	Exon 15 of 15	NP_001427686.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN5	ENST00000376091.8	TSL:2 MANE Select	c.2362C>T	p.Arg788*	stop_gained splice_region	Exon 15 of 15	ENSP00000365259.3	P51795-2
	CLCN5	ENST00000307367.2	TSL:1	c.2152C>T	p.Arg718*	stop_gained splice_region	Exon 12 of 12	ENSP00000304257.2	P51795-1
	CLCN5	ENST00000376108.7	TSL:1	c.2152C>T	p.Arg718*	stop_gained splice_region	Exon 12 of 12	ENSP00000365276.3	P51795-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1079529 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 347577

African (AFR) AF: 0.00 AC: 0 AN: 26086

American (AMR) AF: 0.00 AC: 0 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19257

East Asian (EAS) AF: 0.00 AC: 0 AN: 30102

South Asian (SAS) AF: 0.00 AC: 0 AN: 53700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825382

Other (OTH) AF: 0.00 AC: 0 AN: 45488

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Dent disease type 1 (2)
1	-	-	not provided (1)
1	-	-	X-linked recessive nephrolithiasis with renal failure;C1839874:Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis;C1845168:Hypophosphatemic rickets, X-linked recessive;C1848336:Dent disease type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		1.3
Vest4		0.54
GERP RS		3.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.057
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797044814; hg19: chrX-49856787; COSMIC: COSV56585339;